Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof

Abstract

Indazole compounds for treating various diseases and pathologies are disclosed. More particularly, the present invention concerns the use of an indazole compound or analogs thereof, in the treatment of disorders characterized by the activation of Wnt pathway signaling (e.g., cancer, abnormal cellular proliferation, angiogenesis, Alzheimer's disease, lung disease and osteoarthritis), the modulation of cellular events mediated by Wnt pathway signaling, as well as genetic diseases and neurological conditions/disorders/diseases due to mutations or dysregulation of the Wnt pathway and/or of one or more of Wnt signaling components. Also provided are methods for treating Wnt-related disease states.

1 . A method of treating a genetic disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt thereof having the structure of Formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is -heteroarylR 3 R 4 ; 
         R 2  is selected from the group consisting of H, -heteroarylR 5 , -heterocyclylR 6  and -arylR 7 ; 
         R 3  is selected from the group consisting of H, -heterocyclylR 8 , —NHC(═O)R 9 , —NHSO 2 R 10 , —NR 11 R 12  and —(C 1-6  alkyl)NR 11 R 12 ; 
         with the proviso that R 2  and R 3  are not both H; 
         R 4  is 1-3 substituents each selected from the group consisting of H, halide, —CF 3 , —CN, OR 13  and amino; 
         each R 5  is independently 1-4 substituents each selected from the group consisting of H, C 1-9  alkyl, halide, —CF 3 , —CN, OR 13 , —C(═O)R 1 , amino and —(C 1-6  alkyl)NR 11 R 12 ; 
         each R 6  is independently 1-5 substituents each selected from the group consisting of H, C 1-9  alkyl, halide, —CF 3 , —CN, OR 13  and amino; 
         each R 7  is independently 1-5 substituents each selected from the group consisting of H, C 1-9  alkyl, halide, —CF 3 , —CN, OR 13 , amino, —(C 1-6  alkyl)NHSO 2 R 11 , —NR 12 (C 1-6  alkyl)NR 11 R 12  and —(C 1-6  alkyl)NR 11 R 12 ; 
         R 8  is 1-5 substituents each selected from the group consisting of H, C 1-9  alkyl, halide, —CF 3 , —CN, OR 13  and amino; 
         R 9  is selected from the group consisting of C 1-9  alkyl, -heteroarylR 5 , -heterocyclylR 6 , -arylR 7  and —CH 2 carbocyclyl; 
         R 10  is selected from the group consisting of C 1-9  alkyl, -heteroarylR 5 , -heterocyclylR 6 , -arylR 7 , and -carbocyclylR 14 ; 
         each R 11  is independently selected from C 1-6  alkyl; 
         each R 12  is independently selected from the group consisting of H and C 1-6  alkyl; 
         each R 11  and R 12  are optionally linked to form a five or six membered heterocyclyl ring; 
         each R 13  is independently selected from the group consisting of H and C 1-6  alkyl; 
         R 14  is 1-5 substituents each selected from the group consisting of H, C 1-9  alkyl, halide, —CF 3 , —CN, OR 13  and amino; 
         with the proviso that Formula I is not a structure selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 . The method of  claim 1 , wherein R 1  is pyridine R 3 R 4 . 
     
     
         3 . The method of  claim 2 , wherein R 1  is pyridin-3-ylR 3 R 4 . 
     
     
         4 . The method of  claim 3 , wherein R 3  is —(C 1-6  alkyl)NR 11 R 12 . 
     
     
         5 . The method of  claim 4 , wherein R 3  is —(C 1-2  alkyl)NR 11 R 12 , R 11  is —(C 1-2  alkyl), R 12  is —(C 1-2  alkyl), and R 4  is H. 
     
     
         6 . The method of  claim 4 , wherein R 11  and R 12  are optionally linked to form a five or six membered heterocyclyl ring and R 4  is H. 
     
     
         7 . The method of  claim 6 , wherein the five or six membered heterocyclyl ring is substituted with 1-2 fluorines. 
     
     
         8 . The method of  claim 3 , wherein R 3  is —NHC(═O)R 9 . 
     
     
         9 . The method of  claim 8 , wherein R 4  is H and R 9  is selected from the group consisting of —(C 2-5  alkyl), phenyl, -carbocyclyl, and —CH 2 carbocyclyl. 
     
     
         10 . The method of  claim 3 , wherein R 3  is —NHSO 2 R 10 . 
     
     
         11 . The method of  claim 10 , wherein R 4  is H and R 10  is selected from the group consisting of —(C 1-4  alkyl) and phenyl. 
     
     
         12 . The method of  claim 3 , wherein R 3  is -heterocyclylR 8 . 
     
     
         13 . The method of  claim 12 , wherein R 4  is H and heterocyclyl is selected from the group consisting of morpholine, piperazine and piperidine. 
     
     
         14 . The method of  claim 3 , wherein R 3  is H and R 4  is amino. 
     
     
         15 . The method of  claim 3 , in which R 2  is -heteroarylR 5 . 
     
     
         16 . The method of  claim 15 , in which R 2  is -pyridin-3-ylR 5 . 
     
     
         17 . The method of  claim 16 , in which R 2  is -pyridin-3-ylR 5  and R 5  is 1-2 fluorine atoms. 
     
     
         18 . The method of  claim 15 , in which R 2  is thiopheneR 5 . 
     
     
         19 . The method of  claim 1 , wherein the compound of Formula I is a compound having a structure selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method of  claim 1 , wherein the genetic disease is selected from: polyposis coli, osteoporosis-pseudoglioma syndrome, familial exudative vitreoretinopathy, retinal angiogenesis, early coronary disease, tetra-amelia syndrome, Müllerian-duct regression and virilization, SERKAL syndrome, diabetes mellitus type 2, Fuhrmann syndrome, Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome, odonto-onycho-dermal dysplasia, obesity, split-hand/foot malformation, caudal duplication syndrome, tooth agenesis, Wilms tumor, skeletal dysplasia, focal dermal hypoplasia, autosomal recessive anonychia, neural tube defects, alpha-thalassemia (ATRX) syndrome, fragile X syndrome, ICF syndrome, Angelman syndrome, Prader-Willi syndrome, Beckwith-Wiedemann Syndrome and Rett syndrome, wherein the subject is a human.